Evaluating extent and outcomes of isoniazid exposure during pregnancy among infants born to women living with HIV

Tuberculosis (TB) in pregnancy increases risk of adverse perinatal outcomes, including preeclampsia, preterm birth, low birthweight, and neonatal death. Pregnant women living with HIV (WLHIV) in high burden settings are at elevated risk for TB, despite high antiretroviral therapy (ART) uptake. Isoniazid (INH) as TB preventive therapy (TPT) is routinely offered to pregnant WLHIV at high risk of TB in the US and globally. Safety studies of INH for TB prevention in pregnancy show inconsistent results and call for more robust evaluations of perinatal outcomes following prenatal INH use. To date, no studies have assessed perinatal and infant growth outcomes in the context of quantified cumulative maternal and infant in-utero INH exposure. Further, limited safety data exist for INH use in pregnant WLHIV on newer dolutegravir (DTG)-based ART regimens, which may interact differently with INH. Acquiring safety data from programmatic INH initiation across gestational ages, including 1st trimester, could inform prenatal INH policies for WLHIV on DTG-ART. We currently quantify DTG exposure via drug measurements in breastmilk and hair in an ongoing cohort (n=480) of WLHIV on DTG-ART enrolled in pregnancy and followed with their infants to 36 months to evaluate safety outcomes in Kenya—a setting where there is high uptake of programmatic INH during antenatal care by WLHIV (PrIMA-DTG, P01HD107669 Project 1). PrIMA- DTG built a maternal/infant specimen repository to assess other drug exposures, including INH. Among WLHIV enrolled in PrIMA-DTG, 60% initiated INH during pregnancy, of whom 40% initiated in the 1st trimester and 53% in the 2nd trimester. Using methods to measure HIV drug levels in hair that our team refined in maternal/infant pairs, we will quantify INH exposure in WLHIV receiving INH for TPT in pregnancy and their infants using existing hair samples from the well-characterized PrIMA-DTG cohort (Aim 1) and assess if extent of INH exposure is associated with perinatal and infant outcomes (Aim 2). Our overall goal is to use objective measures to provide comprehensive safety data on INH exposure for pregnant WLHIV on commonly used DTG-ART and their infants. This will be the first large-scale study to directly quantify cumulative maternal INH exposure and fetal transfer in the context of DTG-ART. By leveraging our expertise in perinatal ART safety and TB, high prenatal INH use among WLHIV in Kenya, and an existing maternal/infant specimen repository designed for studies like the one proposed, we are uniquely positioned to execute the proposed aims. This study is intentionally designed to address existing gaps in the safety data of prenatal INH use among WLHIV on DTG-ART. Our findings will inform TB prevention policies and clinical practice in the US and globally by providing INH safety data across gestational ages with objective exposure measures. Project Number: 1R21HD121503-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jillian Pintye (+2 co-PIs) | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $233,250 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 IIDB-C (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD12150301